title: Verification of association of elevated serum IDO enzyme activity with acute rejection and low CD4-ATP levels with infection.
abstract: BACKGROUND
  Both acute rejection (AR) and major infection events (MIE) can reduce long-term allograft survival. We assessed the simultaneous efficacy of serum and urine biomarker indoleamine 2,3-dioxygenase (IDO) enzyme activity and peripheral blood CD4-ATP levels for AR and MIE association, respectively.
  
  
  METHODS
  We prospectively tested 217 blood and 167 urine serial samples, collected monthly for 12 months after transplantation from 29 consecutive children receiving a kidney transplant. The indoleamine 2,3-dioxygenase activity was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with AR, MIE, or stable group (no events) in the next 30 days.
  
  
  RESULTS
  Using absolute cutoffs and allocating to samples to AR, MIE, or stable group, mean serum kyn/trp ratios were significantly elevated in the group that experienced AR (P=0.0007). Similarly, peripheral blood CD4-ATP levels were significantly lower in the group experiencing MIE (P=0.0351). Urine kyn/trp ratios and blood tacrolimus levels were not different between AR and stable groups. Within-subject analyses, accounting for repeated measures in subjects, also showed that, over time, serum kyn/trp ratios were higher before AR (P=0.031) and blood CD4-ATP levels were lower before MIE (P=0.008).
  
  
  CONCLUSIONS
  These results from our pilot discovery group suggest that a panel of biomarkers together can predict overimmunosuppression or underimmunosuppression. Further independent validation in a multicenter cohort is suggested.
authors.affiliation: 1 Divisions of Pediatric Nephrology, University of Florida College of Medicine, Gainesville, FL. 2 Clinical and Translational Science Institute, University of Florida College of Medicine, Gainesville, FL. 3 Department of Health Outcomes and Policy, University of Florida College of Medicine, Gainesville, FL. 4 Hematology-Oncology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL. 5 Address correspondence to: Vikas R. Dharnidharka, M.D., M.P.H., Division of Pediatric Nephrology, Washington University in St. Louis School of Medicine & St. Louis Children's Hospital, Northwest Tower Room 10-119, Campus Box 8116, 660 South Euclid Avenue, St. Louis, MO 63110.
authors.forename: Vikas R
authors.initials: VR
authors.lastname: Dharnidharka
authors.forename: Eihab
authors.initials: E
authors.lastname: Al Khasawneh
authors.forename: Sushil
authors.initials: S
authors.lastname: Gupta
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Shuster
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Theriaque
authors.forename: Amir H
authors.initials: AH
authors.lastname: Shahlaee
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Garrett
mesh_terms: D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000097:blood*; D000293:Adolescent; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002648:Child; D003141:Communicable Diseases / Q000097:blood / Q000201:enzymology / Q000209:etiology* / Q000276:immunology / Q000652:urine; D015536:Down-Regulation; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000201:enzymology / Q000209:etiology* / Q000276:immunology / Q000652:urine; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology; D007737:Kynurenine / Q000097:blood / Q000652:urine; D008137:Longitudinal Studies; D008297:Male; D013058:Mass Spectrometry; D015166:Monitoring, Immunologic / Q000379:methods; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014364:Tryptophan / Q000097:blood / Q000652:urine; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan; D000255:Adenosine Triphosphate